Factor XIa inhibitors

ABSTRACT

The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US15/014708 filed Feb. 6, 2015, whichclaims priority from U.S. Provisional Application Ser. No. 61/938,239,filed Feb. 11, 2014.

BACKGROUND OF THE INVENTION

Factor XIa is a plasma serine protease involved in the regulation ofblood coagulation. While blood coagulation is a necessary and importantpart of the regulation of an organism's homeostasis, abnormal bloodcoagulation can also have deleterious effects. For instance, thrombosisis the formation or presence of a blood clot inside a blood vessel orcavity of the heart. Such a blood clot can lodge in a blood vesselblocking circulation and inducing a heart attack or stroke.Thromboembolic disorders are the largest cause of mortality anddisability in the industrialized world.

Blood clotting is a process of control of the blood stream essential forthe survival of mammals. The process of clotting, and the subsequentdissolution of the clot after wound healing has taken place, commenceafter vascular damage, and can be divided into four phases. The firstphase, vasoconstriction or vasocontraction, can cause a decrease inblood loss in the damaged area. In the next phase, platelet activationby thrombin, platelets attach to the site of the vessel wall damage andform a platelet aggregate. In the third phase, formation of clottingcomplexes leads to massive formation of thrombin, which converts solublefibrinogen to fibrin by cleavage of two small peptides. In the fourthphase, after wound healing, the thrombus is dissolved by the action ofthe key enzyme of the endogenous fibrinolysis system, plasmin.

Two alternative pathways can lead to the formation of a fibrin clot, theintrinsic and the extrinsic pathway. These pathways are initiated bydifferent mechanisms, but in the later phase they converge to give acommon final path of the clotting cascade. In this final path ofclotting, clotting factor X is activated. The activated factor X isresponsible for the formation of thrombin from the inactive precursorprothrombin circulating in the blood. The formation of a thrombus on thebottom of a vessel wall abnormality without a wound is the result of theintrinsic pathway. Fibrin clot formation as a response to tissue damageor an injury is the result of the extrinsic pathway. Both pathwayscomprise a relatively large number of proteins, which are known asclotting factors. The intrinsic pathway requires the clotting factors V,VIII, IX, X, XI and XII and also prekallikrein, high molecular weightkininogen, calcium ions and phospholipids from platelets. The activationof factor XIa is a central point of intersection between the twopathways of activation of clotting. Factor XIa has an important role inblood clotting.

Coagulation is initiated when blood is exposed to artificial surfaces(e.g., during hemodialysis, “on-pump” cardiovascular surgery, vesselgrafts, bacterial sepsis), on cell surfaces, cellular receptors, celldebris, DNA, RNA, and extracellular matrices. This process is alsotermed contact activation. Surface absorption of factor XII leads to aconformational change in the factor XII molecule, thereby facilitatingactivation to proteolytic active factor XII molecules (factor 25 XIIaand factor XIIf). Factor XIIa (or XIIf) has a number of target proteins,including plasma prekallikrein and factor XI. Active plasma kallikreinfurther activates factor XII, leading to an amplification of contactactivation. Alternatively, the serine protease prolylcarboxylpeptidasecan activate plasma kallikrein complexed with high molecular weightkininogen in a multiprotein complex formed on the surface of cells andmatrices (Shariat-Madar et al., Blood, 108:192-199 (2006)). Contactactivation is a surface mediated process responsible in part for theregulation of thrombosis and inflammation, and is mediated, at least inpart, by fibrinolytic-, complement-, kininogen/kinin-, and other humoraland cellular pathways (for review, Coleman, R., “ContactActivationPathway”, Hemostasis and Thrombosis, pp. 103-122, LippincottWilliams & Wilkins (2001); Schmaier, A. H., “Contact Activation”,Thrombosis and Hemorrhage, pp. 105-128 (1998)). The biological relevanceof the contact activation system for thromboembolic 5 diseases issupported by the phenotype of factor XII deficient mice. Morespecifically, factor XII deficient mice were protected from thromboticvascular occlusion in several thrombosis models as well as stroke modelsand the phenotype of the XII deficient mice was identical to XIdeficient mice (Renne et al., J Exp. Med., 202:271-281 (2005);Kleinschmitz et al., J Exp. Med., 203:513-518 (2006)). The fact thatfactor XI is downstream from factor XIIa, combined with the identicalphenotype of the XII and XI deficient mice suggest that the contactactivation system could play a major role in factor XI activation invivo. Plasma kallikrein is a zymogen of a trypsin-like serine proteaseand is present in plasma. The gene structure is similar to that offactor XI. Overall, the amino acid sequence of plasma kallikrein has 58%homology to factor XI. Proteolyticactivation by factor XIIa at aninternal I 389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of plasma kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease 15 inhibitors, including alpha 2 macroglobulin andCl-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Plasma kallikrein cleavesHMWK to liberate bradykinin. Bradykinin release results in increase ofvascular permeability and vasodilation (for review, Coleman, R.,“Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122,Lippincott Williams & Wilkins (2001); Schmaier A. H., “ContactActivation”, Thrombosis and Hemorrhage, pp. 105-128 (1998)).

Factor XIa inhibitor compounds are described in WO2013022814, WO2013022814, WO 2013022818, WO 2013055984, WO2013056034, WO2013056060,WO2013118805. WO2013093484. WO2002042273, WO2002037937, WO2002060894,WO2003015715, WO2004002405, US20040180855, WO2004080971, WO2004094372,US20050228000, US20050282805, WO2005123680, US20090036438,US20120088758, US20060074103, WO2006062972, WO2006076246, US20060154915,US20090062287, US20060183771, WO2007070818, WO2007070816, WO2007070826,WO2008076805, WO2008157162, WO2009114677, WO2011100402, andWO2011100401.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt thereof. The compounds of FormulaI are selective Factor XIa inhibitors or dual inhibitors of Factor XIaand plasma kallikrein, and as such may be useful in the treatment,inhibition or amelioration of one or more disease states that couldbenefit from inhibition of Factor Xia or plasma kallikrein, includingthromboses, embolisms, hypercoagulability or fibrotic changes. Thecompounds of this invention could further be used in combination withother therapeutically effective agents, including but not limited to,other drugs useful for the treatment of thromboses, embolisms,hypercoagulability or fibrotic changes. The invention furthermorerelates to processes for preparing compounds of Formula I, andpharmaceutical compositions which comprise compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the following chemicalformula:

wherein Z is a five or six membered aryl or five or six memberedheteroaryl ring, wherein said aryl or heteroaryl rings are optionallysubstituted with one to three substituents selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, cyano or hydroxy,wherein said alkyl and cycloalkyl groups are optionally substituted withone to three groups independently selected from halo and hydroxy;

-   -   L is selected from the group consisting of CONH, NHC(O) or        heteroaryl, which is optionally substituted with halo or methyl;    -   M is selected from the group consisting of aryl and heteroaryl,        wherein said aryl and heteroaryl groups are optionally        substituted with halo or methyl;    -   R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, cyano or        hydroxy, wherein said alkyl and cycloalkyl groups are optionally        substituted with one to three groups independently selected from        the group consisting of halo and hydroxy;    -   R² is independently selected from the group consisting of        hydrogen, halo, cyano, hydroxy, OR³, C₁₋₆ alkyl, C(O)OH,        C(O)OR³, (R³)C(O)OH, (R³)C(O)OR⁴, NR⁵R⁶, (R³)NR⁵R⁶, NHCOR³,        NHC(O)OR³, NHC(O)OR⁷, NHC(O)O(R³)OR⁴, NHC(O)O(R³)C(O)OH,        (R³)NHC(O)OR⁴, NHCONR⁵R⁶, NHSO₂R³, CONR⁵R⁶, CH₂CONR⁵R⁶ and        NHCONH(R³)R⁷;    -   R³ is hydrogen or C₁₋₆ alkyl, wherein said alkyl is optionally        substituted with one to three halo or hydroxy;    -   R⁴ is hydrogen or C₁₋₆ alkyl, wherein said alkyl is optionally        substituted with one to three halo;    -   R⁵ is hydrogen or C₁₋₆ alkyl;    -   R⁶ is hydrogen or C₁₋₆ alkyl;    -   R⁷ is C₃₋₆ cycloalkyl, heterocyclyl or heteroaryl, wherein said        heteroaryl is optionally substituted with one or two groups        independently selected from the group consisting of halo, C₁₋₃        alkyl and C₃₋₆ cycloalkyl;    -   x is an integer between zero and three;    -   y is an integer between zero and three;        or a pharmaceutically acceptable salt thereof.

In an embodiment of the invention, Z is a five or six membered arylring, which is optionally substituted with one to three substituentsselected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo,cyano or hydroxy, wherein said alkyl and cycloalkyl groups areoptionally substituted with one to three groups independently selectedfrom halo and hydroxy. In a class of the invention, Z is phenyl.

In an embodiment of the invention, L is heteroaryl, which is optionallysubstituted with halo or methyl. In a class of the invention, L isimidazolyl or pyridyl, wherein said imidazolyl and pyridyl areoptionally substituted with chlorine, fluorine or methyl. In a subclassof the invention, L is imidazolyl. In another embodiment of theinvention L is CONH. In another embodiment of the invention L is NHC(O).

In an embodiment of the invention, M is aryl, which is optionallysubstituted with halo or methyl. In a class of the invention, M isphenyl. In a class of the invention, M is phenyl which is substitutedwith halo. In another embodiment of the invention, M is heteroaryl,which is optionally substituted with halo or methyl. In a class of theinvention, M is indazolyl. In another class of the invention, M isbenzothiazolyl. In another class of the invention, M is thiophenyl. Inanother class of the invention, M is isobenzothiazolyl. In another classof the invention, M is quinolinyl.

In an embodiment of the invention, R¹ is hydrogen. In another embodimentof the invention, R¹ is cyclopropyl.

In an embodiment of the invention, R² is H, methyl, R⁷, C(O)OH, NH,NHC(O)OR³ or NHC(O)OR⁷. In another embodiment of the invention, R² isNHC(O)OR³. In a class of the invention, R² is NHC(O)OCH₃. In anotherembodiment of the invention, R² is C(O)OH. In another embodiment of theinvention, R² is H. In another embodiment of the invention, R² is halo.In another embodiment of the invention, R² is or NH₂. In anotherembodiment of the invention, R² is NHC(O)OR⁷. In another embodiment ofthe invention, R² is R⁷. In another embodiment of the invention, R² ismethyl.

In an embodiment of the invention, x is 0. In another embodiment of theinvention, x is 1. In another embodiment of the invention, x is 2. Inanother embodiment of the invention, x is 3.

In an embodiment of the invention, y is 0. In another embodiment of theinvention, y is 1. In another embodiment of the invention, y is 2. Inanother embodiment of the invention, y is 3.

Reference to the preferred classes and subclasses set forth above ismeant to include all combinations of particular and preferred groupsunless stated otherwise.

Specific embodiments of the present invention include, but are notlimited to the compounds identified herein as Examples 1 to 28, orpharmaceutically acceptable salts thereof.

Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound of Formula Ias described above and a pharmaceutically acceptable carrier. Theinvention is also contemplated to encompass a pharmaceutical compositionwhich is comprised of a pharmaceutically acceptable carrier and any ofthe compounds specifically disclosed in the present application. Theseand other aspects of the invention will be apparent from the teachingscontained herein.

The invention also includes compositions for inhibiting loss of bloodplatelets, inhibiting formation of blood platelet aggregates, inhibitingformation of fibrin, inhibiting thrombus formation, inhibiting embolusformation, and treating inflammatory disorders in a mammal, comprising acompound of the invention in a pharmaceutically acceptable carrier.These compositions may optionally include anticoagulants, antiplateletagents, and thrombolytic agents. The compositions can be added to blood,blood products, or mammalian organs in order to effect the desiredinhibitions.

The invention also includes a compositions for preventing or treatingunstable angina, refractory angina, myocardial infarction, transientischemic attacks, atrial fibrillation, thrombotic stroke, embolicstroke, deep vein thrombosis, disseminated intravascular coagulation,ocular build up of fibrin, and reocclusion or restenosis of recanalizedvessels, in a mammal, comprising a compound of the invention in apharmaceutically acceptable carrier. These compositions may optionallyinclude anticoagulants, antiplatelet agents, and thrombolytic agents.

The invention also includes a method for reducing the thrombogenicity ofa surface in a mammal by attaching to the surface, either covalently ornoncovalently, a compound of the invention.

Compounds of the invention are Factor XIa inhibitors and may havetherapeutic value in, for example, preventing coronary artery disease.The compounds are selective Factor XIa inhibitors or dual inhibitors ofFactor XIa and plasma kallikrein.

It will be understood that, as used herein, references to the compoundsof structural Formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate, ascorbate,adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, butyrate, camphorate,camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate,cyclopentane propionate, diethylacetic, digluconate, dihydrochloride,dodecylsulfanate, edetate, edisylate, estolate, esylate,ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate,gluconate, glutamate, glycerophosphate, glycollylarsanilate,hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, 2-hydroxyethanesulfonate,hydroxynaphthoate, iodide, isonicotinic, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate,2-naphthalenesulfonate, napsylate, nicotinate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate,pimelic, phenylpropionic, polygalacturonate, propionate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate,valerate and the like. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof include, but are not limited to, salts derived from inorganicbases including aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, andthe like. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, cyclic amines, dicyclohexyl amines and basicion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. Also, included are the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

These salts can be obtained by known methods, for example, by mixing acompound of the present invention with an equivalent amount and asolution containing a desired acid, base, or the like, and thencollecting the desired salt by filtering the salt or distilling off thesolvent. The compounds of the present invention and salts thereof mayform solvates with a solvent such as water, ethanol, or glycerol. Thecompounds of the present invention may form an acid addition salt and asalt with a base at the same time according to the type of substituentof the side chain.

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I. Centers of asymmetry that are present in thecompounds of Formula I can all independently of one another have (R)configuration or (S) configuration. When bonds to the chiral carbon aredepicted as straight lines in the structural Formulas of the invention,it is understood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. Similarly, when a compound name is recited without achiral designation for a chiral carbon, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. Theproduction of specific stereoisomers or mixtures thereof may beidentified in the Examples where such stereoisomers or mixtures wereobtained, but this in no way limits the inclusion of all stereoisomersand mixtures thereof from being within the scope of this invention.

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I or it can be done on a finalracemic product. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing astereogenic center of known configuration. Where compounds of thisinvention are capable of tautomerization, all individual tautomers aswell as mixtures thereof are included in the scope of this invention.The present invention includes all such isomers, as well as salts,solvates (including hydrates) and solvated salts of such racemates,enantiomers, diastereomers and tautomers and mixtures thereof.

In the compounds of the invention, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the specifically and genericallydescribed compounds. For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds can be prepared without undueexperimentation by conventional techniques well known to those skilledin the art or by processes analogous to those described in the generalprocess schemes and examples herein using appropriateisotopically-enriched reagents and/or intermediates.

When any variable (e.g. R³, etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds. Linesdrawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attachedto any of the suitable atoms on either ring of the bicyclic moiety.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off-target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted” (with one or more substituents)should be understood as meaning that the group in question is eitherunsubstituted or may be substituted with one or more substituents.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I areintended to be included within the scope of the present invention. Inaddition, some of the compounds of the instant invention may formsolvates with water (i.e., a hydrate) or common organic solvents. Suchsolvates and hydrates, particularly the pharmaceutically acceptablesolvates and hydrates, of the instant compounds are likewise encompassedwithin the scope of this invention, along with un-solvated and anhydrousforms.

Reference to the compounds of this invention as those of a specificformula or embodiment, e.g., Formula I or any other generic structuralformula or specific compound described or claimed herein, is intended toencompass the specific compound or compounds falling within the scope ofthe formula or embodiment, including salts thereof, particularlypharmaceutically acceptable salts, solvates of such compounds andsolvated salt forms thereof, where such forms are possible unlessspecified otherwise.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

If the compounds of Formula I simultaneously contain acidic and basicgroups in the molecule the invention also includes, in addition to thesalt forms mentioned, inner salts or betaines (zwitterions). Salts canbe obtained from the compounds of Formula I by customary methods whichare known to the person skilled in the art, for example by combinationwith an organic or inorganic acid or base in a solvent or dispersant, orby anion exchange or cation exchange from other salts. The presentinvention also includes all salts of the compounds of Formula I which,owing to low physiological compatibility, are not directly suitable foruse in pharmaceuticals but which can be used, for example, asintermediates for chemical reactions or for the preparation ofpharmaceutically acceptable salts.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid group or by formation of an ester on anavailable hydroxy group in a compound. Similarly, labile amides can bemade. Pharmaceutically acceptable esters or amides of the compounds ofthis invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO— depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.Examples of pharmaceutically acceptable pro-drug modifications include,but are not limited to, —C₁₋₆alkyl esters and —C₁₋₆alkyl substitutedwith phenyl esters.

Accordingly, the compounds within the generic structural formulas,embodiments and specific compounds described and claimed hereinencompass salts, all possible stereoisomers and tautomers, physicalforms (e.g., amorphous and crystalline forms), solvate and hydrate formsthereof and any combination of these forms, as well as the saltsthereof, pro-drug forms thereof, and salts of pro-drug forms thereof,where such forms are possible unless specified otherwise.

Except where noted herein, the term “alkyl” is intended to include bothbranched- and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. Commonly used abbreviationsfor alkyl groups are used throughout the specification, e.g. methyl, maybe represented by conventional abbreviations including “Me” or CH₃ or asymbol that is an extended bond as the terminal group, e.g.

ethyl may be represented by “Et” or CH₂CH₃, propyl may be represented by“Pr” or CH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂CH₃,etc. “C₁₋₄ alkyl” (or “C₁₋₄C₄ alkyl”) for example, means linear orbranched chain alkyl groups, including all isomers, having the specifiednumber of carbon atoms. For example, the structures

have equivalent meanings C₁₋₄ alkyl includes n-, iso-, sec- and t-butyl,n- and isopropyl, ethyl and methyl. If no number is specified, 1-4carbon atoms are intended for linear or branched alkyl groups.

Except where noted herein, “alkanol” is intended to include aliphaticalcohols having the specified number of carbon atoms, such as methanol,ethanol, propanol, etc., where the —OH group is attached at anyaliphatic carbon, e.g., propan-1-ol, propan-2-ol, etc.

Except where noted, the term “cycloalkyl” means a monocyclic saturatedaliphatic hydrocarbon group having the specified number of carbon atoms.For example, “cycloalkyl” includes cyclopropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and so on.

Except where noted, the term “halogen” means fluorine, chlorine, bromineor iodine.

Except where noted, the term “heteroaryl”, as used herein, represents astable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in eachring, wherein at least one ring is aromatic and contains from 1 to 4heteroatoms selected from the group consisting of O, N and S. Heteroarylgroups within the scope of this definition include but are not limitedto: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl,methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl,isoquinolinyl, oxazolyl, and tetra-hydroquinoline. If the heteroarylcontains nitrogen atoms, it is understood that the correspondingN-oxides thereof are also encompassed by this definition.

Except where noted, the term “heterocycle” or “heterocyclyl” as usedherein is intended to mean a 5- to 10-membered nonaromatic ring, unlessotherwise specified, containing from 1 to 4 heteroatoms selected fromthe group consisting of O, N, S, SO, or SO₂ and includes bicyclicgroups. “Heterocyclyl” therefore includes, but is not limited to thefollowing: piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl,tetrahydrothiophenyl and the like. If the heterocycle contains anitrogen, it is understood that the corresponding N-oxides thereof arealso encompassed by this definition.

Except where noted, the term “aryl” is intended to mean any stablemonocyclic or bicyclic carbon ring of up to 12 atoms in each ring,wherein at least one ring is aromatic. Examples of such aryl elementsinclude phenyl, naphthyl, tetrahydronaphthyl and indanyl.

“Celite®” (Fluka) diatomite is diatomaceous earth, and can be referredto as “celite”.

Except where noted herein, structures containing substituent variablessuch as variable “R” below:

which are depicted as not being attached to any one particular bicyclicring carbon atom, represent structures in which the variable can beoptionally attached to any bicyclic ring carbon atom. For example,variable R shown in the above structure can be attached to any one of 6bicyclic ring carbon atoms i, ii, iii, iv, v or vi.

Except where noted herein, bicyclic ring systems include fused ringsystems, where two rings share two atoms, and spiro ring systems, wheretwo rings share one atom.

The invention also includes derivatives of the compound of Formula I,acting as prodrugs and solvates. Prodrugs, following administration tothe patient, are converted in the body by normal metabolic or chemicalprocesses, such as through hydrolysis in the blood, to the compound ofFormula 1. Such prodrugs include those that demonstrate enhancedbioavailability, tissue specificity, and/or cellular delivery, toimprove drug absorption of the compound of Formula I. The effect of suchprodrugs may result from modification of physicochemical properties suchas lipophilicity, molecular weight, charge, and other physicochemicalproperties that determine the permeation properties of the drug.

The preparation of pharmaceutically acceptable salts from compounds ofthe Formula (I) capable of salt formation, including theirstereoisomeric forms is carried out in a manner known per se. With basicreagents such as hydroxides, carbonates, hydrogencarbonates, alkoxidesand ammonia or organic bases, for example, trimethyl- or triethylamine,ethanolamine, diethanolamine or triethanolamine, trometamol oralternatively basic amino acids, for example lysine, ornithine orarginine, the compounds of the Formula (I) form stable alkali metal,alkaline earth metal or optionally substituted ammonium salts. If thecompounds of the Formula (I) have basic groups, stable acid additionsalts can also be prepared using strong acids. For this, inorganic andorganic acids such as hydrochloric, hydrobromic, sulfuric, hemisulfuric,phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic,4-bromobenzenesulfonic, cyclohexylamidosulfonic,trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic,tartaric, succinic, glycerolphosphoric, lactic, malic, adipic, citric,fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acidare suitable.

The invention also relates to medicaments containing at least onecompound of the Formula (I) and/or of a pharmaceutically acceptable saltof the compound of the Formula (I) and/or an optionally stereoisomericform of the compound of the Formula (I) or a pharmaceutically acceptablesalt of the stereoisomeric form of the compound of Formula (I), togetherwith a pharmaceutically suitable and pharmaceutically acceptablevehicle, additive and/or other active substances and auxiliaries.

Anticoagulant therapy is indicated for the treatment and prevention of avariety of thrombotic conditions, particularly coronary artery andcerebrovascular disease. Those experienced in this field are readilyaware of the circumstances requiring anticoagulant therapy. The term“patient” used herein is taken to mean mammals such as primates, humans,sheep, horses, cattle, pigs, dogs, cats, rats, and mice.

Factor XIa inhibition is useful not only in the anticoagulant therapy ofindividuals having thrombotic conditions, but is useful wheneverinhibition of blood coagulation is required such as to preventcoagulation of stored whole blood and to prevent coagulation in otherbiological samples for testing or storage. Thus, the Factor XIainhibitors can be added to or contacted with any medium containing orsuspected of containing thrombin and in which it is desired that bloodcoagulation be inhibited, e.g., when contacting the mammal's blood withmaterial selected from the group consisting of vascular grafts, stents,orthopedic prosthesis, cardiac prosthesis, and extracorporealcirculation systems.

Compounds of the invention may be useful for treating or preventingvenous thromboembolism (e.g., obstruction or occlusion of a vein by adetached thrombus; obstruction or occlusion of a lung artery by adetached thrombus), cardiogenic thromboembolism (e.g., obstruction orocclusion of the heart by a detached thrombus), arterial thrombosis(e.g., formation of a thrombus within an artery that may causeinfarction of tissue supplied by the artery), atherosclerosis (e.g.,arteriosclerosis characterized by irregularly distributed lipiddeposits) in mammals, and for lowering the propensity of devices thatcome into contact with blood to clot blood.

Examples of venous thromboembolism which may be treated or preventedwith compounds of the invention include obstruction of a vein,obstruction of a lung artery (pulmonary embolism), deep vein thrombosis,thrombosis associated with cancer and cancer chemotherapy, thrombosisinherited with thrombophilic diseases such as Protein C deficiency,Protein S deficiency, antithrombin III deficiency, and Factor V Leiden,and thrombosis resulting from acquired thrombophilic disorders such assystemic lupus erythematosus (inflammatory connective tissue disease).Also with regard to venous thromboembolism, compounds of the inventionmay be useful for maintaining patency of indwelling catheters.

Examples of cardiogenic thromboembolism which may be treated orprevented with compounds of the invention include thromboembolic stroke(detached thrombus causing neurological affliction related to impairedcerebral blood supply), cardiogenic thromboembolism associated withatrial fibrillation (rapid, irregular twitching of upper heart chambermuscular fibrils), cardiogenic thromboembolism associated withprosthetic heart valves such as mechanical heart valves, and cardiogenicthromboembolism associated with heart disease.

Examples of arterial thrombosis include unstable angina (severeconstrictive pain in chest of coronary origin), myocardial infarction(heart muscle cell death resulting from insufficient blood supply),ischemic heart disease (local anemia due to obstruction (such as byarterial narrowing) of blood supply), reocclusion during or afterpercutaneous transluminal coronary angioplasty, restenosis afterpercutaneous transluminal coronary angioplasty, occlusion of coronaryartery bypass grafts, and occlusive cerebrovascular disease. Also withregard to arterial thrombosis, compounds of the invention may be usefulfor maintaining patency in arteriovenous cannulas.

Examples of atherosclerosis include arteriosclerosis.

The compounds of the invention may also be kallikrein inhibitors andespecially useful for treatment of hereditary angioedema.

Examples of devices that come into contact with blood include vasculargrafts, stents, orthopedic prosthesis, cardiac prosthesis, andextracorporeal circulation systems.

The medicaments according to the invention can be administered by oral,inhalative, rectal or transdermal administration or by subcutaneous,intraarticular, intraperitoneal or intravenous injection. Oraladministration is preferred. Coating of stents with compounds of theFormula (I) and other surfaces which come into contact with blood in thebody is possible.

The invention also relates to a process for the production of amedicament, which comprises bringing at least one compound of theFormula (I) into a suitable administration form using a pharmaceuticallysuitable and pharmaceutically acceptable carrier and optionally furthersuitable active substances, additives or auxiliaries.

Suitable solid or galenical preparation forms are, for example,granules, powders, coated tablets, tablets, (micro)capsules,suppositories, syrups, juices, suspensions, emulsions, drops orinjectable solutions and preparations having prolonged release of activesubstance, in whose preparation customary excipients such as vehicles,disintegrants, binders, coating agents, swelling agents, glidants orlubricants, flavorings, sweeteners and solubilizers are used. Frequentlyused auxiliaries which may be mentioned are magnesium carbonate,titanium dioxide, lactose, mannitol and other sugars, talc, lactose,gelatin, starch, cellulose and its derivatives, animal and plant oilssuch as cod liver oil, sunflower, peanut or sesame oil, polyethyleneglycol and solvents such as, for example, sterile water and mono- orpolyhydric alcohols such as glycerol.

The dosage regimen utilizing the Factor XIa inhibitors is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular compound or saltthereof employed. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

Oral dosages of the Factor XIa inhibitors, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, morepreferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day(unless specified otherwise, amounts of active ingredients are on freebase basis). For example, an 80 kg patient would receive between about0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200mg/day, and most preferably 8-40 mg/kg/day. A suitably preparedmedicament for once a day administration would thus contain between 0.8mg and 2.4 g, preferably between 2 mg and 600 mg, more preferablybetween 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg,10 mg, 20 mg and 40 mg. Advantageously, the Factor XIa inhibitors may beadministered in divided doses of two, three, or four times daily. Foradministration twice a day, a suitably prepared medicament would containbetween 0.4 mg and 4 g, preferably between 1 mg and 300 mg, morepreferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg,e.g., 4 mg, 5 mg, 10 mg and 20 mg.

Intravenously, the patient would receive the active ingredient inquantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day. Suchquantities may be administered in a number of suitable ways, e.g. largevolumes of low concentrations of active ingredient during one extendedperiod of time or several times a day, low volumes of highconcentrations of active ingredient during a short period of time, e.g.once a day. Typically, a conventional intravenous formulation may beprepared which contains a concentration of active ingredient of betweenabout 0.01-1.0 mg/ml, e.g. 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml, andadministered in amounts per day of between 0.01 ml/kg patient weight and10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg. In oneexample, an 80 kg patient, receiving 8 ml twice a day of an intravenousformulation having a concentration of active ingredient of 0.5 mg/ml,receives 8 mg of active ingredient per day. Glucuronic acid, L-lacticacid, acetic acid, citric acid or any pharmaceutically acceptableacid/conjugate base with reasonable buffering capacity in the pH rangeacceptable for intravenous administration may be used as buffers. Thechoice of appropriate buffer and pH of a formulation, depending onsolubility of the drug to be administered, is readily made by a personhaving ordinary skill in the art.

Compounds of the Formula (I) can be administered both as a monotherapyand in combination with other therapeutic agents, includingantithrombotics (anticoagulants and platelet aggregation inhibitors),thrombolytics (plasminogen activators), other profibrinolytically activesubstances, hypotensives, blood sugar regulators, lipid-lowering agentsand antiarrhythmics.

The Factor XIa inhibitors can also be co-administered with suitableanticoagulants, including, but not limited to, other Factor XIainhibitors, thrombin inhibitors, thrombin receptor antagonists, factorVIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factorXIIa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12antagonists), fibrinogen receptor antagonists (e.g. to treat or preventunstable angina or to prevent reocclusion after angioplasty andrestenosis), other anticoagulants such as aspirin, and thrombolyticagents such as plasminogen activators or streptokinase to achievesynergistic effects in the treatment of various vascular pathologies.Such anticoagulants include, for example, apixaban, dabigatran,cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen,prasugrel, rivaroxaban, and semuloparin. For example, patients sufferingfrom coronary artery disease, and patients subjected to angioplastyprocedures, would benefit from coadministration of fibrinogen receptorantagonists and thrombin inhibitors. Factor XIa inhibitors may beadministered first following thrombus formation, and tissue plasminogenactivator or other plasminogen activator is administered thereafter.

Alternatively or additionally, one or more additional pharmacologicallyactive agents may be administered in combination with a compound of theinvention. The additional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) that is active in the body,including pro-drugs that convert to pharmaceutically active form afteradministration, which is different from the compound of the invention,and also includes free-acid, free-base and pharmaceutically acceptablesalts of said additional active agents when such forms are soldcommercially or are otherwise chemically possible. Generally, anysuitable additional active agent or agents, including but not limited toanti-hypertensive agents, additional diuretics, anti-atheroscleroticagents such as a lipid modifying compound, anti-diabetic agents and/oranti-obesity agents may be used in any combination with the compound ofthe invention in a single dosage formulation (a fixed dose drugcombination), or may be administered to the patient in one or moreseparate dosage formulations which allows for concurrent or sequentialadministration of the active agents (co-administration of the separateactive agents). Examples of additional active agents which may beemployed include but are not limited to angiotensin converting enzymeinhibitors (e.g, alacepril, benazepril, captopril, ceronapril,cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril,lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril,temocapril, or trandolapril); angiotensin II receptor antagonists alsoknown as angiotensin receptor blockers or ARBs, which may be infree-base, free-acid, salt or pro-drug form, such as azilsartan, e.g.,azilsartan medoxomil potassium (EDARBI®), candesartan, e.g., candesartancilexetil (ATACAND®), eprosartan, e.g., eprosartan mesylate (TEVETAN®),irbesartan (AVAPRO®), losartan, e.g., losartan potassium (COZAAR®),olmesartan, e.g, olmesartan medoximil (BENICAR®), telmisartan(MICARDIS®), valsartan (DIOVAN®), and any of these drugs used incombination with a thiazide-like diuretic such as hydrochlorothiazide(e.g., HYZAAR®, DIOVAN HCT®, ATACAND HCT®), etc.); potassium sparingdiuretics such as amiloride HCl, spironolactone, epleranone,triamterene, each with or without HCTZ; neutral endopeptidase inhibitors(e.g., thiorphan and phosphoramidon); aldosterone antagonists;aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635); endothelin receptorantagonists; vasodilators (e.g. nitroprusside); calcium channel blockers(e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine,gallopamil, niludipine, nimodipine, nicardipine); potassium channelactivators (e.g., nicorandil, pinacidil, cromakalim, minoxidil,aprilkalim, loprazolam); sympatholitics; beta-adrenergic blocking drugs(e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol,metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol);alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alphamethyldopa); central alpha adrenergic agonists; peripheral vasodilators(e.g. hydralazine); lipid lowering agents, e.g., HMG-CoA reductaseinhibitors such as simvastatin and lovastatin which are marketed asZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitorsafter administration, and pharmaceutically acceptable salts of dihydroxyopen ring acid HMG-CoA reductase inhibitors such as atorvastatin(particularly the calcium salt sold in LIPITOR®), rosuvastatin(particularly the calcium salt sold in CRESTOR®), pravastatin(particularly the sodium salt sold in PRAVACHOL®), and fluvastatin(particularly the sodium salt sold in LESCOL®); a cholesterol absorptioninhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination withany other lipid lowering agents such as the HMG-CoA reductase inhibitorsnoted above and particularly with simvastatin (VYTORIN®) or withatorvastatin calcium; niacin in immediate-release or controlled releaseforms, and particularly niacin in combination with a DP antagonist suchas laropiprant and/or with an HMG-CoA reductase inhibitor; niacinreceptor agonists such as acipimox and acifran, as well as niacinreceptor partial agonists; metabolic altering agents including insulinsensitizing agents and related compounds for the treatment of diabetessuch as biguanides (e.g., metformin), meglitinides (e.g., repaglinide,nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride,glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones alsoreferred to as glitazones (e.g., pioglitazone, rosiglitazone), alphaglucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidaseinhibitors, (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin,saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids(e.g., bromocriptine), combination medications such as JANUMET®(sitagliptin with metformin), and injectable diabetes medications suchas exenatide and pramlintide acetate; inhibitors of glucose uptake, suchas sodium-glucose transporter (SGLT) inhibitors and its variousisoforms, such as SGLT-1, SGLT-2 (e.g., ASP-1941, TS-071, BI-10773,tofogliflozin, LX-4211, canagliflozin, dapagliflozin, ertugliflozin,ipragliflozin and remogliflozin), and SGLT-3; or with other drugsbeneficial for the prevention or the treatment of the above-mentioneddiseases including but not limited to diazoxide; and including thefree-acid, free-base, and pharmaceutically acceptable salt forms,pro-drug forms, e.g., esters, and salts of pro-drugs of the abovemedicinal agents, where chemically possible. Trademark names ofpharmaceutical drugs noted above are provided for exemplification of themarketed form of the active agent(s); such pharmaceutical drugs could beused in a separate dosage form for concurrent or sequentialadministration with a compound of the invention, or the active agent(s)therein could be used in a fixed dose drug combination including acompound of the invention.

Typical doses of Factor XIa inhibitors of the invention in combinationwith other suitable anti-platelet agents, anticoagulation agents, orthrombolytic agents may be the same as those doses of Factor XIainhibitors administered without coadministration of additionalanti-platelet agents, anticoagulation agents, or thrombolytic agents, ormay be substantially less that those doses of thrombin inhibitorsadministered without coadministration of additional anti-plateletagents, anticoagulation agents, or thrombolytic agents, depending on apatient's therapeutic needs.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to treat (i.e. prevent, inhibit or ameliorate) thethromboembolic and/or inflammatory disease condition or treat theprogression of the disease in a host.

The compounds of the invention are preferably administered alone to amammal in a therapeutically effective amount. However, the compounds ofthe invention can also be administered in combination with an additionaltherapeutic agent, as defined below, to a mammal in a therapeuticallyeffective amount. When administered in a combination, the combination ofcompounds in preferably, but not necessarily, a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul. 1984, 22, 27-55, occurs when the effect (in this case, inhibitionof the desired target) of the compounds when administered in combinationis greater than the additive effect of the compounds when administeredalone as a single agent. In general, a synergistic effect is mostclearly demonstrated at suboptimal concentrations of the compounds.Synergy can be in terms of lower cytotoxicity, increased anticoagulanteffect, or some other beneficial effect of the combination compared withthe individual components.

By “administered in combination” or “combination therapy” it is meantthat the compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The present invention is not limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in therelevant art and are intended to fall within the scope of the appendedclaims.

For purposes of this specification, the following abbreviations have theindicated meanings:

-   -   ACN=Acetonitrile    -   DCE=1,2-dichloroethane    -   DMF=dimethylformamide    -   DCM=dichloromethane    -   DIPEA=N,N-Diisopropylethylamine    -   EtOAc=ethyl acetate    -   EDC=N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   RP HPLC=Reverse Phase High Pressure Liquid Chromatography    -   Hex=hexanes    -   HOBt=Hydroxybenzotriazole    -   Me=methyl    -   MgSO₄=magnesium sulfate    -   MP-Cyanoborohydride=macroporous polymer-supported        cyanoborohydride    -   rt or RT=room temperature    -   THF=tetrahydrofuran    -   NMP=N-Methyl-2-pyrrolidone    -   Pd(OAc)₂=Palladium (II) acetate    -   TFA=Trifluoroacetic acid    -   HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate Methanaminium

Also, TLC is thin layer chromatography; Ts is tosyl; UV is ultraviolet;W is watts; wt. % is percentage by weight; x g is times gravity; α_(D)is the specific rotation of polarized light at 589 nm; ° C. is degreesCelsius; % w/v is percentage in weight of the former agent relative tothe volume of the latter agent.

LCMS Conditions

System: Waters Acquity UPLC/MS, Electrospray positive ion mode; Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 micron; Mobile Phase: A:H2O/0.05% TFA, B: ACN/0.05% TFA; Gradient: 0-1.8 min, 5-99% B; FlowRate: 0.8 mL/min; UV: 254 nm.

General Methods

The compounds of the present invention can be readily produced fromknown compounds or commercially available compounds by, for example,known processes described in published documents, and produced byproduction processes described below. The present invention is notlimited to the production processes described below. The invention alsoincludes processes for the preparation of compounds of the invention.

It should be noted that, when compounds of the present inventionsynthesized has a reactive group such as hydroxy group, amino group,carboxyl group, or thiol group as its substituent, such group may beadequately protected with a protective group in each reaction step andthe protective group may be removed at an adequate stage. The process ofsuch introduction and removal of the protective group may be adequatelydetermined depending on the group to be protected and the type of theprotective group, and such introduction and removal are conducted, forexample, by the process described in the review section of Greene, T.W., et. al., “Protective Groups in Organic Synthesis”, 2007, 4th Ed.,Wiley, New York, or Kocienski, P., “Protecting Groups” 1994, Thieme.

Step 1-1

A compound represented by formula (i-b) can be produced by allowing thesuitably substituted (i-a) to react with a coupling agent by awell-known process or a process similar to that described in publisheddocuments (Stille, J. K., Angew. Chem. 1986, Vol 98, pp 504, forexample), using a coupling agent such as allyltributyl tin in thepresence of a Pd(O) catalyst and cesium fluoride, in a solvent which isinactive to the reaction such as dioxane or toluene at a temperature inthe range of 0° C. to the solvent reflux temperature.

Step 1-2

A compound represented by formula (i-c) can be produced by allowing thesuitably substituted (i-b) to react with a oxidative agent by awell-known process or a process similar to that described in publisheddocuments (Org. Lett., 2004, 3, 2835-2838; Org. Synth. Coll. 1990, Vol.7: pp 168; for example), ozonolysis in a ozonizer or reacting withreagents such as potassium osmate and sodium periodate, in a solventwhich is inactive to the reaction such as a water: acetone mixture atambient temperature.

Step 1-3

A compound represented by formula (i-e) can be produced by allowing thesuitably substituted aldehyde (i-c) to react with a reducing agent inthe presence of an amine (i-d) by a well-known process or a processsimilar to that described in published documents (Stuart Warren and PaulWyatt (2008). Organic synthesis: the disconnection approach (2nd ed.)Oxford: Wiley-Blackwell. p. 54; for example), by treating with sodiumcyanoborohydride or sodium triacetoxyborohydride in the presence of theamine and acetic acid in a solvent which is inactive to the reactionsuch as methanol or chlorinated solvent such as DCE or a mixture of themat a temperature in the range of 0° C., rt or the solvent refluxtemperature.

Step 1-4

A compound represented by formula (i-f) can be produced by allowing thesuitably substituted acid (i-e) to react by a well-known process or aprocess similar to that described in published documents, procedures andreferences in patent publication WO1985000605 A1, for example, in thepresence of a reducing agent such as sodium borohydride in the presenceof a Cobalt catalyst in a solvent which is inactive to the reaction,e.g., methanol, at a temperature in the range of 0° C. to the solventreflux temperature.

Example 1METHYL[(7S)-7-[6-(AMINOMETHYL)-1-OXO-3,4-DIHYDROISOQUINOLIN-2(1H)-YL]-2-OXO-1,2,3,4,5,6,7,9-OCTAHYDRO-11,8-(AZENO)-1,9-BENZODIAZACYCLOTRIDECIN-14-YL]CARBAMATE

Step 1:

Commercially available methyl 2-chloro-4-cyanobenzoate 1A (750 mg, 3.83mmol), bis(tri-tert-butylphosphine)palladium(0) (196 mg, 0.383 mmol),and cesium fluoride (1281 mg, 8.44 mmol) were added to a flask equippedwith a stirbar. The flask was evacuated under vacuum and then refilledwith nitrogen. Allyltributyltin (1397 mg, 4.22 mmol) and dioxane (19 mL)were added via a syringe, and then reaction mixture was stirred at 100°C. overnight. After cooling at rt, the reaction mixture was concentratedunder vacuum, and water was added. It was then extracted with EtOAc (3×,30.0 mL), and the combined extracts were dried over Na₂SO₄, filtered,dried over Na₂SO₄ and concentrated under vacuum. The crude was purifiedby silica gel chromatography (hexanes/EtOAC, 0-50%) to give methyl2-allyl-4-cyanobenzoate 1B.

Step 2:

The methyl 2-allyl-4-cyanobenzoate 1B (2.3 g, 11.43 mmol) was dissolvedin EtOH (460 ml). The solution was then transferred to the ozonolysisvessel (Ozonolysis Ozonia Model OZAT CFS-1/3 2G). The solution wasallowed to cool to −20° C. The ozone generator was started by setting itat 17%, and ensured that the gas was bubbling through the solution.After only 5 minutes of ozone, the solution changed from clear andcolorless, to a deep yellow. The reaction was run for an additional 15minutes. During this time, the solution turned a deep brown-orange anddimethyl sulfide (0.930 ml, 12.57 mmol) was charged to the vessel, andthe reaction was allowed to warm to 0° C. The reaction was concentratedand the crude 1C was taken directly to next step.

Step 3:

Methyl 4-cyano-2-(2-oxoethyl)benzoate 1C (90.0 mg, 0.443 mmol) and theamine 1D (167 mg, 0.443 mmol, prepared as in Scheme B below) weredissolved in MeOH (1004 μl): DCE (1004 μl) mixture. MP-cyanoborohydride(575 mg, 1.329 mmol) was then added followed by acetic acid (76 μl,1.329 mmol), and the mixture was stirred at rt for 4 h. The resin wasfiltered, rinsed with MeOH, and the filtrate was concentrated undervacuum. The residue was dissolved in EtOAc, washed with sat aqueousNaHCO₃, dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude was purified by silica gel chromatography (hexanes/EtOAC, 0-100%)to give the reductive amination product as a pale-yellow oil. To thereductive amination product in DCM (1000 μL) was added TFA (1000 μl,12.98 mmol) at rt. The resulting mixture was stirred at rt for 1 hbefore concentrating under vacuum. Water was then added, extracted withEtOAc (2×, 30.0 mL), and the combined organic layers were dried overNa₂SO₄, filtered and concentrated under vacuum. The crude 1E was useddirectly in the next step.

Step 4:

(S)-4-(2-(6-cyano-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-phenylpropanamido)benzoicacid 1E (173 mg, 0.394 mmol) and cobalt(II) chloride hexahydrate (46.8mg, 0.197 mmol) in MeOH (3937 μl) was added to sodium borohydride (44.7mg, 1.181 mmol) carefully. The resulting black mixture was stirred at rtfor 3 h before it was quenched by addition of concentrated HCl (5.00μL). The mixture was stirred at 0° C. for 10 min and at rt for 45 min.Diethylenetriamine (200 μL) was then added, and the mixture was stirredfor a further 15 min. The reaction mixture was concentrated undervacuum, and the crude residue was purified by RP HPLC (Gilson on a19×100 mm, Waters XBridge C18 column, 5μ particle size, linear gradient,standard 5% ACN/H₂O to 100% ACN/H₂O buffering with 0.05% TFA @ flow rate30 mL/min over 10 min) to give4-({(2S)-2-[6-(aminomethyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]-3-phenylpropanoyl}amino)benzoicacid trifluoroacetate 1 as a white powder. MS (ESI) m/z 444.43 (M+H)

PREPARATION OF INTERMEDIATE (S)-TERT-BUTYL4-(2-AMINO-3-PHENYLPROPANAMIDO)BENZOATE 1D

To the commercially available tert-butyl 4-aminobenzoate (200 mg, 1.035mmol) in THF (5175 μl) was added commercially available(S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanoic acid (310 mg, 1.035mmol), DIPEA (462 μl, 2.59 mmol) and HATU (472 mg, 1.242 mmol) at rt.The reaction mixture was stirred at the same temperature for 2 h, andTHF was evaporated under vacuum. The crude was purified by silica gelchromatography (hexanes/EtOAC, 0-100%) to give the amide-couplingproduct. The amide-coupling product was dissolved in MeOH (5.50 mL), andPd—C (50 mg, 0.470 mmol) was added carefully. The resulting mixture wasevacuated under vacuum, purged with hydrogen (3×) and stirred at rtovernight under 1 atm of hydrogen. Upon completion by LC-MS, thereaction mixture was filtered through a pad of celite, and the filtratewas concentrated under vacuum to give crude (S)-tert-butyl4-(2-amino-3-phenylpropanamido)benzoate 1D.

Example 2 (S)-METHYL(4-(2-(1-(6-(AMINOMETHYL)-1-OXO-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-2-PHENYLETHYL)-1H-IMIDAZOL-5-YL)PHENYL)CARBAMATE2,2,2-TRIFLUOROACETATE

The intermediate 1D in step 3 of Example 1 is replaced with amine 1F(prepared as directed below) and is treated with conditions in Step 3and 4 to provide Example 2. MS (ESI) m/z 496.55 (M+H).

PREPARATION OF INTERMEDIATE 1F: (S)-METHYL(4-(2-(1-AMINO-2-PHENYLETHYL)-1H-IMIDAZOL-5-YL)PHENYL)CARBAMATEDIHYDROCHLORIDE

Commercially available(S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid 1F-1 (1000 mg,3.77 mmol), methyl (4-(2-chloroacetyl)phenyl)carbamate 1F-2 (prepared asin patent publication WO 2007/070826 A2; 858 mg, 3.77 mmol) and cesiumcarbonate (1228 mg, 3.77 mmol) were mixed in DMF (7538 μl) and stirredovernight. Upon completion by LC-MS, the mixture was diluted with waterand extracted with Et₂O (2×, 50.0 mL). The combined organic layers werewashed with water, brine, dried over Na₂SO₄, filtered and concentratedunder vacuum. The crude 1F-3 was used directly in the next step.

(S)-2-(4-((methoxycarbonyl)amino)phenyl)-2-oxoethyl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate 1F-3 (1721 mg, 3.77mmol) and ammonium acetate (1162 mg, 15.08 mmol) in toluene (37.7 mL)were heated to 150° C. under microwave irradiation for 30 min. Uponcompletion by LC-MS, the reaction mixture was diluted with EtOAc, washedwith brine, dried over Na₂SO₄, filtered and concentrated under vacuum.The crude was purified by silica gel chromatography (hexanes/EtOAc,0-100%) to give the imidazole compound. To the imidazole compound wasadded 4.0 M HCl in dioxane (12.0 mL, 146 mmol) at rt, and the reactionwas stirred at the same temperature for 1 h. EtOAc was added toprecipitate products. The precipitates were vacuum-filtered to givecrude (S)-methyl(4-(2-(1-amino-2-phenylethyl)-1H-imidazol-5-yl)phenyl)carbamatedihydrochloride 1F.

The following compounds were prepared using methods analogous to thosedescribed in the preceding examples:

LCMS hu Factor XIa Ex. Structure [M + H] Ki 1

444.4  44 nM 2

496.5 116 nM 3

430.5 308 nM 4

444.4 176 nM 5

473.2 546 nM 6

531.3  14 nM 7

440.3 246 nM

Example 8

To a solution of(S)-2-(6-cyano-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-phenylpropanoicacid (30 mg, 0.094 mmol) in THF (1 ml) was added DIPEA (0.050 ml, 0.281mmol) and HOBt (21.5 mg, 0.140 mmol). To this solution was added2-methylbenzo[d]thiazol-6-amine (30.8 mg, 0.187 mmol) and polystyrenecarbodiimide resin last (176 mg, 0.283 mmol). The reaction mixture wasput on a shaker overnight.

To the reaction was added polystyrene trisamine resin (85 mg, 0.375mmol) and let stir 3 hours. The reaction was filtered and the resinwashed well with THF. The solvent was removed and the residue taken onto the next step as is.

Under a nitrogen atmosphere in a glove box, cobalt(II) chloridehexahydrate (11.18 mg, 0.047 mmol) was added to compound(S)-2-(6-cyano-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-methylbenzo[d]thiazol-6-yl)-3-phenylpropanamide(43.9 mg, 0.094 mmol). To this was added methanol (1 ml) and carefullyadded sodium borohydride (14.23 mg, 0.376 mmol). Reaction was allowed tostir at RT for 4 hours.

UPLC-MS shows there was still starting material present. Added moresodium borohydride (12 mg). After 3½ hr, reaction appears to becomplete. Reaction was removed from the glove box and cooled in an icebath. The reaction was quenched with cold HCl (10 μl, 0.122 mmol). Letstir 5 min and removed from the ice. Let stir at RT for 30 min andquenched with diethylenetriamine (200 μL, 1.851 mmol). The reactionwhich was cloudy, clears up. Let stir another 15 min and removed solventby Genevac. The reaction was purified by reverse phase chromatographywith a 15-50 gradient/acetonitrile: water with ammonium hydroxidemodifier. (UPLC-MS M+1=471.2)

LCMS hu Factor XIa Ex. Structure [M + H] Ki 8

471.1 907.5 nM 9

418.2 1078 nM 10

441.5 4135 nM 11

510.4 84 nM 12

478.3 53 nM 13

455.1 151 nM 14

573.3 435 nM 15

584.3 506 nM 16

606.3  68 17

530.4 244 18

534.0 2073 nM 19

466.1 68.90 nM 20

466.1 94.3 nM 21

481.2 254.2 nM 22

481.3 239.6 nM 23

480.1 1077 nM 24

451.2 1077 nM 25

507.1 220.6 nM 26

480.2 207.0 nM 27

471.2 284.4 nM 28

471.1 1474 nM

Example 29

Step 1:

Commercially available 6-bromoisochroman-1-one 29A (20 g, 88 mmol), insulfuric acid (155 ml, 2907 mmol) at 0° C. was treated with mixture ofnitric acid (25.9 ml, 617 mmol) and sulfuric acid (4 mL). The resultingslurry was stirred for 45 min. at room temp. Resulting mixture waspoured on to ice and subsequently stirred for another 45 min and formeda precipitate. The solution was filtered and the recovered solid waswashed with cold water. The solid material was pumped to dryness. 1H NMRanalysis of the solid material indicated the formation of two productswhere, one of the product had the nitro functional group on the 5position (top spot on TLC), while the second product (the bottom spot onTLC) had the nitro product on the 7-position. The crude was purified bysilica gel chromatography (hexanes/EtOAc, 0-50%) to give6-bromo-5-nitroisochroman-1-one 29B.

Step 2:

6-bromo-5-nitroisochroman-1-one 29B (3.7 g, 13.60 mmol) and tin(II)chloride dihydrate (15.34 g, 68.0 mmol) in Ethanol (6 ml) were heated to150° C. under microwave irradiation for 60 min. Upon completion byLC-MS, ethanol was removed, the reaction mixture was diluted with DCM,treated with 1M aq NaOH, dried over Na₂SO₄, filtered and concentratedunder vacuum. The crude was purified by silica gel chromatography(hexanes/EtOAc, 0-50%) to give 5-amino-6-bromoisochroman-1-one 1C.

Step 3:

To a stirred light green suspension of copper(II) chloride (0.722 g,5.37 mmol) in ACN (15 mL) was added tert-butyl nitrite (0.715 ml, 5.37mmol) in one portion. It was stirred at room temperature for 0.5 h underN₂. 5-amino-6-bromoisochroman-1-one 29C (1.3 g, 5.37 mmol) in dry ACN(25 mL) was added drop wise over a course of 10 min. The resultingsolution was stirred for 1 h at room temp. 1M HCl was poured into thereaction mix. It was then extracted with EtOAc (3×,10 mL) and thecombined organic extracts were washed with sat. NaHCO₃ (2×,10 mL) andbrine (2×, 5 mL), Combined EtOAc were dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude was purified by silica gelchromatography (hexanes and EtOAc, 0-50%) to give6-bromo-7-chloroisochroman-1-one 29D.

Step 4:

To 6-bromo-7-chloroisochroman-1-one 29D (990 mg, 3.79 mmol) wasdissolved in DMF (10 mL). Cyanocopper (339 mg, 3.79 mmol) was added anddegassed with N₂ sparge for 5 minutes, heated overnight at 150° C. Thesolution was allowed to cool to rt. Water (10 mL) was added, extractedwith EtOAc (2×, 50 mL), combined EtOAc washed with brine (1×, 50 mL),dried over Na₂SO₄, filtered and concentrated. The crude was purified bysilica gel chromatography (hexanes/EtOAc, 0-50%) to give5-chloro-1-oxoisochroman-6-carbonitrile 29E.

Step 5:

5-chloro-1-oxoisochroman-6-carbonitrile 29E (480 mg, 2.312 mmol),potassium cyclopropyltrifluoroborate (342 mg, 2.312 mmol),diacetoxypalladium (51.9 mg, 0.231 mmol),dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (216 mg,0.462 mmol) and potassium carbonate (959 mg, 6.94 mmol) in toluene (10ml) and Water (1 ml) were heated to 85° C. overnight. After cooling atrt, the reaction mixture was diluted with EtOAc and filtered overcelite, concentrated under vacuum. The crude was purified by silica gelchromatography (hexanes/EtOAc, 0-50%) to give5-cyclopropyl-1-oxoisochroman-6-carbonitrile 29F.

Step 6:

Cyclopropyl-1-oxoisochroman-6-carbonitrile 29F (106 mg, 0.497 mmol) inMeOH (4 ml) and THF (6 ml) was added lithium hydroxide (1.243 ml, 2.486mmol) and stirred at rt for 0.5 h. Reaction mixture was extracted withwater (10 mL) and EtOAc (10 mL). EtOAc layer was discarded. Aq layer wasacidify to pH 5-6, extracted with EtOAc (3× 10 mL). Combined EtOAclayers were dried over Na₂SO₄. The reaction was concentrated undervacuum on cold water and the 29G taken directly to next step.

Step 7:

Cyano-3-cyclopropyl-2-(2-hydroxyethyl)benzoic acid 29G (91 mg, 0.394mmol) was added to sulfurous dichloride (431 μl, 5.90 mmol) at −10° C.slowly to keep internal temp at or around −3° C. After 20 min at 0° C.the mixture was heated to reflux for 4 hrs. Volatiles were removed andthe residue was mixed twice with toluene, concentrated and the2-(2-chloroethyl)-4-cyano-3-cyclopropylbenzoyl chloride (29H) was takendirectly to next step.

Step 8:

To a solution of amine 29I (S)-methyl(4-(2-(1-amino-2-phenylethyl)-1H-imidazol-5-yl)phenyl)carbamatehydrochloride (prepared as in WO 2007/070826A2 and previously describedprocedures) (88 mg, 0.237 mmol) in THF (3 mL) was added dropwise asolution of 2-(2-chloroethyl)-4-cyano-3-cyclopropylbenzoyl chloride 29H(53 mg, 0.198 mmol) and then sodium hydride (40 mg, 1.000 mmol) wasadded to the suspension and heated at 65° C. for 3 h. The reaction wasquenched with ice and extracted with EtOAc. The reaction wasconcentrated and purified by chromatography Analogix column (70%EtOAc/hexanes) to give (S)-methyl(4-(2-(1-(6-cyano-5-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)phenyl)carbamate29J.

Step 9:

To 29J (S)-methyl(4-(2-(1-(6-cyano-5-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)phenyl)carbamate(15 mg, 0.028 mmol) and cobalt(II) chloride hexahydrate (5 mg, 0.021mmol) in MeOH (500 μl) was added sodium tetrahydroborate (5 mg, 0.132mmol) carefully. The resulting black mixture was stirred at rt overnightbefore it was quenched by addition of 3M HCl (30 μL). The mixture wasstirred at 0° C. for 10 min and at rt for 5 min. Diethylenetriamine (50μL) was then added, and the mixture was stirred for a further 15 min.The reaction mixture was concentrated under vacuum, and the cruderesidue was purified by reverse phase HPLC (0-100% water/CAN with 0.05%TFA) to get the pure(S)-methyl(4-(2-(1-(6-(aminomethyl)-5-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)phenyl)carbamate2,2,2-trifluoroacetate 29.

LCMS hu Factor XIa Ex. Structure [M + H] Ki 29

536.1 198 nM

Factor XIa Assay

The effectiveness of compounds of the present invention as inhibitors ofCoagulation Factor XIa can be determined using a relevant purifiedserine protease, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Assays were conducted at roomtemperature or at 37° C. Hydrolysis of the substrate resulted in releaseof amino trifluoromethylcoumarin (AFC), which was monitoredspectrofluorometrically by measuring the increase in emission at 510 nmwith excitation at 405 nm. A decrease in the rate of fluorescence changein the presence of inhibitor is indicative of enzyme inhibition. Suchmethods are known to one skilled in the art. The results of this assayare expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 150 mM NaCl, 5 mM CaCl₂, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 40 pM (SekisuiDiagnostics) and the synthetic substrate, Z-Gly-Pro-Arg-AFC, TFA salt(Sigma #C0980) at a concentration of 100 μM.

Activity assays were performed by diluting a stock solution of substrateat least tenfold to a final concentration ≦0.1 K_(m) into a solutioncontaining enzyme or enzyme equilibrated with inhibitor. Times requiredto achieve equilibration between enzyme and inhibitor were determined incontrol experiments. Initial velocities of product formation in theabsence (V_(o)) or presence of inhibitor (V_(i)) were measured. Assumingcompetitive inhibition, and that unity is negligible compared K_(m)/[S],[I]/e, and [I]/e (where [S], [I], and e respectively represent the totalconcentrations, of substrate, inhibitor and enzyme), the equilibriumconstant (K_(i)) for dissociation of the inhibitor from the enzyme canbe obtained from the dependence of V_(o)/V_(i) on [I] shown in thefollowing equation.V _(o) /V _(i)=1+[I]/K _(i)

The activities shown by this assay indicate that the compounds of theinvention may be therapeutically useful for treating or preventingvarious cardiovascular and/or cerebrovascular thromboembolic conditionsin patients suffering from unstable angina, acute coronary syndrome,refractory angina, myocardial infarction, transient ischemic attacks,atrial fibrillation, stroke such as thrombotic stroke or embolic stroke,venous thrombosis, coronary and cerebral arterial thrombosis, cerebraland pulmonary embolism, atherosclerosis, deep vein thrombosis,disseminated intravascular coagulation, and reocclusion or restenosis ofrecanalized vessels.

What is claimed is:
 1. A compound of the formula:

wherein Z is a five or six membered aryl or five or six memberedheteroaryl ring, wherein said aryl or heteroaryl rings are optionallysubstituted with one to three substituents selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, cyano or hydroxy,wherein said alkyl and cycloalkyl groups are optionally substituted withone to three groups independently selected from halo and hydroxy; L isselected from the group consisting of CONH, NHC(O) or heteroaryl, whichis optionally substituted with halo or methyl; M is selected from thegroup consisting of aryl and heteroaryl, wherein said aryl andheteroaryl groups are optionally substituted with halo or methyl; R¹ ishydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, cyano or hydroxy, whereinsaid alkyl and cycloalkyl groups are optionally substituted with one tothree groups independently selected from the group consisting of haloand hydroxy; R² is independently selected from the group consisting ofhydrogen, halo, cyano, hydroxy, R⁷, OR³, C₁₋₆ alkyl, C(O)OH, C(O)OR³,(R³)C(O)OH, (R³)C(O)OR⁴, NR⁵R⁶, (R³)NR⁵R⁶, NHCOR³, NHC(O)OR³, NHC(O)OR⁷,NHC(O)O(R³)R⁷, NHC(O)O(R³)OR⁴, NHC(O)O(R³)C(O)OH, (R³)NHC(O)OR⁴,NHCONR⁵R⁶, NHSO₂R³, CONR⁵R⁶, CH₂CONR⁵R⁶ and NHCONH(R³)R⁷; R³ is hydrogenor C₁₋₆ alkyl, wherein said alkyl is optionally substituted with one tothree halo or hydroxy; R⁴ is hydrogen or C₁₋₆ alkyl, wherein said alkylis optionally substituted with one to three halo; R⁵ is hydrogen or C₁₋₆alkyl; R⁶ is hydrogen or C₁₋₆ alkyl; R⁷ is C₃₋₆ cycloalkyl, heterocyclylor heteroaryl, wherein said heteroaryl is optionally substituted withone or two groups independently selected from the group consisting ofhalo, C₁₋₃ alkyl and C₃₋₆ cycloalkyl; x is an integer between zero andthree; y is an integer between zero and three; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein L is CONH;or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 wherein L is heteroaryl, which is optionally substituted with halo ormethyl; or a pharmaceutically acceptable salt thereof.
 4. The compoundof claim 1 wherein L is imidazolyl or pyridyl, wherein said imidazolyland pyridyl are optionally substituted with chlorine, fluorine ormethyl; or a pharmaceutically acceptable salt thereof.
 5. The compoundof claim 1 wherein M is phenyl; or a pharmaceutically acceptable saltthereof.
 6. The compound of claim 1 wherein R¹ is hydrogen orcyclopropyl; or a pharmaceutically acceptable salt thereof.
 7. Thecompound of claim 1 wherein R² is H, methyl, R⁷, C(O)OH, NH, NHC(O)OR³or NHC(O)OR⁷; or a pharmaceutically acceptable salt thereof.
 8. Thecompound of claim 1 wherein x is 1; or a pharmaceutically acceptablesalt thereof.
 9. The compound of claim 1 wherein Z is phenyl; or apharmaceutically acceptable salt thereof.
 10. The compound of claim 1selected from:

or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 12. A method for inhibiting thrombus formation inblood or treating thrombus formation in blood comprising administering acomposition of claim 11 to a mammal in need of thereof.
 13. A method forpreventing thrombus formation in blood comprising administering acomposition of claim 11 to a mammal in need thereof.
 14. A method oftreating venous thromboembolism and pulmonary embolism in a mammalcomprising administering a composition of claim 11 to a mammal in needthereof.
 15. A method of treating deep vein thrombosis in a mammalcomprising administering a composition of claim 11 to a mammal in needthereof.
 16. A method of treating thromboembolic stroke in a humancomprising administering a composition of claim 11 to a mammal in needthereof.